1-aryl-2-hydroxyethyl amides as potassium channel openers

ABSTRACT

The present invention provides novel aryl hydroxyethyl amides and related derivatives having the general Formula I  
                 
 
     wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and A are as defined in the specification, or a nontoxic pharmaceutically acceptable salt, solvate or hydrate thereof which are openers or activators of KCNQ potassium channels. The present invention also provides pharmaceutical compositions comprising said aryl hydroxyethyl amides and to the method of treatment of disorders sensitive to KCNQ potassium channel opening activity such as migraine or a migraine attack, bipolar disorders, epilepsy, acute and chronic pain and anxiety.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This is a non-provisional application which claims the benefit ofU.S. Provisional Application No. 60/428,338 filed Nov. 22, 2002.

FIELD OF THE INVENTION

[0002] The present invention is directed to novel aryl hydroxyethylamide derivatives which are modulators of KCNQ potassium channels andare therefore useful in treating disorders responsive to the modulationof the potassium channels. The present invention also provides a methodof treatment with the novel aryl hydroxyethyl amide derivatives and topharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION

[0003] Potassium (K⁺) channels are considered to be the most diverseclass of ion channels and have several critical roles in cell function.This has been demonstrated in neurons where K⁺ channels are responsible,in part, for determining cell excitability by contributing to membranerepolarization following depolarization, resting membrane potential, andregulation of neurotransmitter release. The M-current has long beendescribed, by electrophysiology recording methods and by pharmacology,as a dominant conductance in controlling neuronal excitability.Pharmacological activation or suppression of M-currents by smallmolecules could have profound effects in controlling neuronalexcitability. Recently, Wang et al., Science, 282:1890-1893, (1998)reported that co-assembly of the KCNQ2 and KCNQ3 potassium channelsunderlies the native M-current in neurons.

[0004] Activation or opening of the KCNQ channel(s), particularly theKCNQ2 or KCNQ2/3 channel(s), mutated or wild type, may prove to bebeneficial in increasing hyperpolarization of neurons, thereby resultingin protection from abnormal synchronous firing during a migraine attack.The present invention provides a solution to the problem of abnormalsynchronous firing of neurons related to migraine headache bydemonstrating that modulators, preferably openers, of KCNQ potassiumchannels increases hyperpolarization of neurons which protects againstabnormal synchronous neuron firing involved in migraine attacks.

[0005] Although the symptom pattern varies among migraine sufferers, theseverity of migraine pain justifies a need for vigorous, yet safe andeffective, treatments and therapies for the great majority of cases.Needed in the art are agents that can be used to combat and relievemigraine (and diseases similar to and mechanistically related tomigraine), and even prevent the recurrence of migraine. Also needed areanti-migraine agents which are effective in the treatment of acutemigraine, as well as in the prodrome phase of a migraine attack. Thus, aclear goal in the art is to discover new, safe, nontoxic and effectiveanti-migraine compounds for use as drugs, and in anti-migrainecompositions and treatments.

[0006] Because migraine afflicts a large percentage of the population,there is a need to discover compounds and agents that are useful intherapeutics and treatments, and as components of pharmaceuticalcompositions, for reducing, ameliorating, or alleviating the pain anddiscomfort of migraine headache and other symptoms of migraine. Thepresent invention satisfies such a need by providing compounds thatfunction as openers of the KCNQ family of potassium channel proteins toserve as anti-migraine agents or drugs and to comprise compositions totreat migraine, as described herein.

[0007] A broad range of cinnamide compounds are known and new compoundscontinue to be reported with a broad range of utility. Some of thesecompounds can be found in the disclosures of WO 00/07993 published Feb.17, 2000, EP 810220A1, published Dec. 3, 1997, U.S. Pat. No. 4,927,838issued May 22, 1990 to Guthrie, et al., U.S. Pat. No. 6,046,239 issuedApr. 4, 2000 to Lennox, et al., WO 00.42013, published Jul. 20, 2000, WO01/10381 published Feb. 15, 2001, WO 01/10380 published Feb. 15, 2001,JP45-14291 published May 21, 1970, and JP2-138159 published May 28,1990. The compounds described in these patents are distinct from thoseof the present invention.

SUMMARY OF THE INVENTION

[0008] The present invention provides novel aryl hydroxyethyl amides andrelated derivatives having the general Formula I

[0009] wherein R¹, R², R¹, R⁴, R⁵, R⁶, R⁷ and A are as defined below, ora nontoxic pharmaceutically acceptable salt, solvate or hydrate thereofwhich are openers or activators of KCNQ potassium channels. The presentinvention also provides pharmaceutical compositions comprising said arylhydroxyethyl amides and to the method of treatment of disorderssensitive to KCNQ potassium channel opening activity such as migraine ora migraine attack, bipolar disorders, epilepsy, acute and chronic painand anxiety.

DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention provides novel aryl hydroxyethyl amides andrelated derivatives which are modulators of the KCNQ potassium channelsand which have the general Formula I or a pharmaceutically acceptablesalt thereof

[0011] wherein R¹ is selected from the group consisting of pyridinyl,3-quinolinyl, 2-thienyl, furanyl, C₃₋₆ cycloalkyl and phenyl optionallysubstituted with substituent independently selected from the groupconsisting of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl,trifluoromethoxy and nitro; A is —CH═CH— or —CH₂)_(n)—; R² is hydrogenor hydroxymethyl; n is an integer of 0, 1 or 2; R⁴ is selected from thegroup consisting of di(C₁₋₄ alkyl)amino, trifluoromethoxy and optionallysubstituted morpholin-4-yl, morpholin-4-ylmethyl, pyridinyl,pyrimidinyl, piperazinyl, and pyrazinyl with one or two substituents inwhich said substituent is independently selected from the groupconsisting of C₁₋₄ alkyl, aminomethyl, hydroxymethyl, chloro or fluoro;R⁵ is hydrogen or fluoro; or R⁴ and R⁵ taken together is —CH═CH—CH═CH—optionally substituted with a substituent independently selected fromthe group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl andtrifluoromethoxy; and R³, R⁶, and R⁷ are each independently hydrogen orfluoro.

[0012] The present invention also provides a method for the treatment oralleviation of disorders associated with KCNQ potassium channelpolypeptides and, in particular, human KCNQ potassium channelpolypeptides in a mammal in need thereof which comprises administeringtogether with a conventional adjuvant, carrier or diluent atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt thereof. Preferably, the compounds ofFormula I are useful in the treatment of migraine or a migraine attack,cluster headaches, bipolar disorder, convulsions, mania, acute mania,epilepsy, anxiety, depression, schizophrenia, functional boweldisorders, stroke, traumatic brain injury, multiple sclerosis,neurodegenerative disorders or alleviating pain such as musculoskeletalpain, post operative pain, surgical pain, inflammatory pain, neuropathicpain such as diabetic neuropathy and pain associated with cancer andfibromyalgia.

[0013] The term “pain” as used herein and in the claims means all typesof acute and chronic pain, such as neuropathic pain, post-operativepain, chronic lower back pain, cluster headaches, herpes neuralgia,phantom limb pain, central pain, dental pain, opioid-resistant pain,visceral pain, surgical pain, bone injury pain, pain during labor anddelivery, pain resulting from burns, including sunburn, post partumpain, migraine, angina pain, and genitourinary tract-related painincluding cystitis and the term also is intended to include nociceptivepain or nociception.

[0014] The term “C₁₋₄ alkyl” as used herein and in the claims meansstraight or branched chain alkyl groups such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl. The term “C₁₋₄ alkoxy” asused herein and in the claims means an oxygen substituted with straightor branched chain alkyl groups and includes groups such as methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tert-butoxy. Theterm “halogen” as used herein and in the claims is intended to includebromine, chlorine, iodine and fluorine.

[0015] As the compounds of the present invention contain a substitutedcarbon-carbon double bond as part of the structure, the compounds of theinvention exist in either of two geometric isomeric forms, namely as cisor trans isomers. Preferred are the trans isomers in which the groupR^(i) and the amide group, C(O)NH, are trans to each other when A is—CH═CH—. As the compounds of the present invention possess an asymmetriccarbon atom, such as the carbon adjacent to the amide nitrogen and towhich the phenyl is attached, the present invention includes theracemate as well as the individual enantiomeric forms of the compoundsof Formula I as described herein and in the claims. Preferredembodiments of compounds of Formula I include the racemate, a singleenantiomer, and in certain instances a single enantiomer wherein thecarbon adjacent to the amide nitrogen and to which the phenyl isattached has the (S) stereochemistry. Mixtures of isomers of thecompounds of Formula I or chiral precursors thereof can be separatedinto individual isomers according to methods which are known per se,e.g. fractional crystallization, adsorption chromatography or othersuitable separation processes. Resulting racemates can be separated intoantipodes in the usual manner after introduction of suitablesalt-forming groupings, e.g. by forming a mixture of diastereosiomericsalts with optically active salt-forming agents, separating the mixtureinto diastereomeric salts and converting the separated salts into thefree compounds. The enantiomeric forms may also be separated byfractionation through chiral high pressure liquid chromatographycolumns, according to procedures described herein.

[0016] Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms including hydrated forms suchas monohydrate, dihydrate, trihydrate, hemihydrate, tetrahydrate and thelike. The products may be true solvates, while in other cases, theproducts may merely retain adventitious solvent or be a mixture ofsolvate plus some adventitious solvent. It should be appreciated bythose skilled in the art that solvated forms are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

[0017] In the method of the present invention, the term “therapeuticallyeffective amount” means the total amount of each active component of themethod that is sufficient to show a meaningful patient benefit, i.e.,amelioration or healing of conditions which respond to modulation of theKCNQ potassium channels. When applied to an individual activeingredient, administered alone, the term refers to that ingredientalone. When applied to a combination, the term refers to combinedamounts of the active ingredients that result in the therapeutic effect,whether administered in combination, serially or simultaneously. Theterm “KCNQ” as used herein and in the claims means the family of KCNQ2,KCNQ3, KCNQ4, and KCNQ5 potassium channel polypeptides as well asheteromultimers of different individual family members which include butare not limited to KCNQ2/3, KCNQ2/5 and KCNQ3/5. The terms “treat,treating, treatment” as used herein and in the claims means preventing,alleviating or ameliorating diseases and/or symptoms associated withdysfunction of cellular membrane polarization and conductance of humanKCNQ2, KCNQ3, KCNQ4, and KCNQ5 potassium channel polypeptides and, inparticular, migraine and/or symptoms that precede a full-blown migraineattack, neuropathic pain, mania and anxiety.

[0018] The general procedures used to synthesize intermediates and thecompounds of Formula I are described in Reaction Schemes 1-4 and areillustrated in the preparations and examples. Reasonable variations ofthe described procedures, which would be evident to one skilled in theart, are intended to be within the scope of the present invention.

[0019] Reaction Scheme 1 depicts the preparation of cinnamic acidderivatives useful as intermediates in the synthesis of compounds ofFormula I. Step 1 of Reaction Scheme 1 depicts the Wittig reaction of anappropriate aldehyde or ketone of Formula II with an appropriate Wittigreagent to provide the methyl ester of Formula III. Hydrolysis of themethyl ester of Formula III can be accomplished using an appropriatebase such as sodium hydroxide or lithium hydroxide in an appropriatesolvent followed by acidification with an appropriate acid such as 1Nhydrochloric acid to provide the cinnamic acid of Formula IV.

[0020] Reaction Scheme 2 depicts an alternative preparation of acinnamic acid derivative of Formula IV which can be then used to preparecompounds within general Formula I.

[0021] Reaction Scheme 3 depicts a general method useful for thepreparation of amines of Formula VIII which are useful intermediates forthe preparation of compounds of Formula I. Compound of Formula VI wasconverted to compound of Formula VII, wherein X is CO(O)^(t)Bu orC(O)OCH₂C₆H₅, via catalytic asymmetric aminohydroxylation following theprocedures of Sharpless and coworkers (J. Amer. Che. Soc., 1998, Vol.120, No. 6, pp1207-1217). Deprotection of compound of Formula VII can beaccomplished by hydrolysis under acidic conditions such as 1Nhydrochloric acid or catalytic hydrogenation to afford compound ofFormula VIII.

[0022] Reaction Scheme 4 depicts an alternative method useful for thepreparation of amines of Formula X. Compound of Formula VI underwentepoxidation under epoxidation conditions such as mCPBA(meta-chloroperoxybenzoic acid) or methyltrioxorhenium and hydrogenperoxide to give compound of Formula IX. The compound of Formula IX canbe converted to compound of Formula VIII by treatment withazidotrimethylsilane followed by aluminum isopropyoxide.

[0023] Reaction Scheme 5 depicts the preparation of compounds of generalFormula I from the acid of general Formula X and amine of generalFormula VIII. The coupling of the acid, X, and amine, VIII is carriedout by methodology well known in the art for the conversion of an acidand an amine to form an amide. Useful reactive derivatives of the acidof Formula X include, but are not limited to, activated esters, reactivemixed anhydrides, and acid halides (such as the acid chloride, preparede.g. with thionyl chloride or oxalyl chloride). A preferred method is tocondense the acid of Formula X with the amine of Formula VIII in thepresence of an appropriate condensing agent, for example,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) ordicyclohexylcarbodiimide (DCC), and a basic tertiary amine, such as4-dimethylaminopyridine (DMAP), in an inert solvent such asdichloromethane. The more preferred method is to couple the acid ofFormula X with the amine of Formula VIII in the presence of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (EDC) inthe presence of 4-dimethylaminopyridine (DMAP), triethylamine (Et₃N), indichloromethane.

[0024] In one embodiment, the present invention includes compounds ofFormula I or a pharmaceutically acceptable salt thereof

[0025] wherein R¹ is selected from the group consisting of pyridinyl,3-quinolinyl, 2-thienyl, furanyl, C₃₋₆ cycloalkyl and phenyl optionallysubstituted with substituent independently selected from the groupconsisting of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl,trifluoromethoxy and nitro; A is —CH═CH— or —(CH₂)_(n)—; R² is hydrogenor hydroxymethyl; n is an integer of 0, 1 or 2; R⁴ is selected from thegroup consisting of di(C₁₋₄ alkyl)amino, trifluoromethoxy and optionallysubstituted morpholin-4-yl, morpholin-4-ylmethyl, pyridinyl,pyrimidinyl, piperazinyl, and pyrazinyl with one or two substituents inwhich said substituent is independently selected from the groupconsisting of C₁₋₄ alkyl, aminomethyl, hydroxymethyl, chloro or fluoro;R⁵ is hydrogen or fluoro; or R⁴ and R⁵ taken together is —CH═CH—CH═CH—optionally substituted with a substituent independently selected fromthe group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl andtrifluoromethoxy; and R³, R⁶, and R⁷ are each independently hydrogen orfluoro.

[0026] In a preferred embodiment, the present invention includescompounds of Formula Ia or a pharmaceutically acceptable salt thereof

[0027] wherein R¹ is selected from the group consisting of pyridinyl,3-quinolinyl, 2-thienyl, furanyl, C₃₋₆ cycloalkyl and phenyl optionallysubstituted with substituent independently selected from the groupconsisting of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl,trifluoromethoxy and nitro; A is —CH═CH— or —(CH₂)_(n)—; R² is hydrogen;n is an integer of 0, 1 or 2; R⁴ is selected from the group consistingof di(C₁₋₄ alkyl)amino, trifluoromethoxy and optionally substitutedmorpholin-4-yl, morpholin-4-ylmethyl, pyridinyl, pyrimidinyl,piperazinyl, and pyrazinyl with one or two substituents in which saidsubstituent is independently selected from the group consisting of C₁₋₄alkyl, aminomethyl, hydroxymethyl, chloro or fluoro; R⁵ is hydrogen orfluoro; or R⁴ and R⁵ taken together is —CH═CH—CH═CH— optionallysubstituted with a substituent independently selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl andtrifluoromethoxy; and R³, R⁶, and R⁷ are each independently hydrogen orfluoro.

[0028] Preferred compounds for use in the method of the presentinvention include the compounds of Formula I listed below:

[0029](R)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-propionamide;

[0030](R)-3-(2-fluoro-phenyl)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]-acrylamide;

[0031](R)-3-(3-fluoro-phenyl)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]-acrylamide;

[0032](R)-3-(2,4-difluoro-phenyl)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]-acrylamide;

[0033](R)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-3-(2-fluorophenyl)-acrylamide;

[0034](R)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-3-(3-fluorophenyl)-acrylamide;

[0035](R)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-3-(4-fluorophenyl)-acrylamide;

[0036](R)-3-(2,4-difluoro-phenyl)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-acrylamide;

[0037](R)-3-(3-fluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-acrylamide;

[0038](R)-3-(4-fluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-acrylamide;

[0039](R)-3-(2,4-difluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-acrylamide;

[0040](R)-3-(3,4-difluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-acrylamide;

[0041] (R)-4-fluoro-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-benzamide;

[0042] (R)-2,3-difluoro-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-benzamide;

[0043] (R)-2,4-difluoro-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-benzamide;

[0044] (R)-3,4-difluoro-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-benzamide;

[0045](R)-2-(2,4-difluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-acetamide;

[0046](R)-3-(2-fluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-propionamide;

[0047](R)-3-(3-fluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-propionamide;

[0048](R)-3-(4-fluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-propionamide;

[0049](R)-3-(2,4-difluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-propionamide;

[0050](R)-3-(2-fluoro-phenyl)-N-[2-hydroxy-1-(7-methoxy-naphthalen-2-yl)-ethyl]-acrylamide;

[0051](R)-3-(3-fluoro-phenyl)-N-[2-hydroxy-1-(7-methoxy-naphthalen-2-yl)-ethyl]-acrylamide;

[0052](R)-3-(4-fluoro-phenyl)-N-[2-hydroxy-1-(7-methoxy-naphthalen-2-yl)-ethyl]-acrylamide;

[0053](R)-3-(2,4-difluoro-phenyl)-N-[2-hydroxy-1-(7-methoxy-naphthalen-2-yl)-ethyl]-acrylamide;

[0054](1R,2S)-N-(2,3-dihydroxy-1-naphthalen-2-yl-propyl)-3-(2-fluoro-phenyl)-acrylamide;

[0055](1R,2S)-3-(2,4-difluoro-phenyl)-N-(2,3-dihydroxy-1-naphthalen-2-yl-propyl)-acrylamide;

[0056](1R,2S)-3-(3,4-difluoro-phenyl)-N-(2,3-dihydroxy-1-naphthalen-2-yl-propyl)-acrylamide;and

[0057](1R,2)-3-(3,5-difluoro-phenyl)-N-(2,3-dihydroxy-1-naphthalen-2-yl-propyl)-acrylamide;

[0058] or a pharmaceutically acceptable salt thereof.

Biological Activity

[0059] KCNQ Methods and Results

[0060] Potassium (K⁺) channels are structurally and functionally diversefamilies of K⁺-selective channel proteins which are ubiquitous in cells,indicating their central importance in regulating a number of key cellfunctions [Rudy, B., Neuroscience, 25: 729-749 (1988)]. While widelydistributed as a class, K⁺ channels are differentially distributed asindividual members of this class or as families. [Gehlert, D. R., etal., Neuroscience, 52: 191-205 (1993)]. In general, activation of K⁺channels in cells, and particularly in excitable cells such as neuronsand muscle cells, leads to hyperpolarization of the cell membrane, or inthe case of depolarized cells, to repolarization. In addition to actingas an endogenous membrane voltage clamp, K⁺ channels can respond toimportant cellular events such as changes in the intracellularconcentration of ATP or the intracellular concentration of calcium(Ca²⁺). The central role of K⁺ channels in regulating numerous cellfunctions makes them particularly important targets for therapeuticdevelopment. [Cook, N. S., Potassium channels: Structure,classification, function and therapeutic potential. Ellis Horwood,Chinchester (1990)]. One class of K⁺ channels, the KCNQ familyexemplified by KCNQ2, KCNQ2/3 heteromultimers, and KCNQ5, is regulatedby transmembrane voltage and plays a potentially important role in theregulation of neuronal excitability [Biervert, C., et al., Science, 279:403-406 (1998); Lerche, C. et al., J. Biol. Chem. 275:22395-22400(2000); Wang, H. et al., Science, 282:1890-1893 (1998)].

[0061] An opener of KCNQ channels, such as the KCNQ2 and KCNQ2/3 channelopener retigabine, exerts its cellular effects by increasing the openprobability of these channels [Main J., Mol Pharmacol 58(2):253-62(2000); Wickenden, A. et al., Mol. Pharm. 58:591-600 (2000)]. Thisincrease in the opening of individual KCNQ channels collectively resultsin the hyperpolarization of cell membranes, particularly in depolarizedcells, produced by significant increases in whole-cell KCNQ-mediatedconductance.

[0062] Whole-cell patch-clamp recordings were made from an HEK 293stable cell line expressing mKCNQ2 channels, maintained in culture for1-2 days. Patch pipettes had initial resistances of 2.5-4 MΩ. Currentswere recorded with an EPC-9 amplifier (HEKA, Lambrecht, Germany)controlled with software (Pulse, HEKA) run on a standard lab PC. Seriesresistance compensation was used during current recording, and set at80%. The series resistance (R) and cell capacitance (C) were determinedelectronically by subtracting the capacitive currents at the onset andoffset of a 5 mV voltage step. The cancellation of whole-cell capacitivetransients was virtually complete in all cells. Analog current signalswere low-pass filtered at 2.9 kHz using a four-pole Bessel filter −3 dB)and stored on a local network server computer at a sampling rate of 1.5kHz. All recordings were performed at room temperature (20-22° C.). Thepipette solution contained (mM): KCl, 150; CaCl₂, 2.5; EGTA, 5; MgCl₂,1; HEPES, 10; pH to 7.3 with KOH, and Osmolality of 290-300 mOsm. Theextracellular solution contained (mM): NaCl, 140; KCl, 2.5; CaCl₂, 2.5;MgCl₂, 1; glucose, 10; HEPES, 10; pH to 7.3 with NaOH, and Osmolality of305-310 mOsm

[0063] For analysis of agents effects on mKCNQ2 currents, the rawcurrent records were displayed on the digital oscilloscope of the Pulsesoftware application. Concentration response data were generated bymeasuring the difference in the steady-state amplitude of current in thepresence of compound at the end of a 600 ms voltage-clamp step from aholding potential of −80 mV. The concentration-response data were fittedwith Hill-type equations:

I=I _(max)/(1+EC ₅₀ /[A] ^(nH)),

[0064] where I is the steady-state current at a given concentration ofagonist [A]; and I_(max), EC₅₀ and nH are parameters estimated from thecurve fit. In some cases the concentration-response data were fittedwith equations consisting of the sum of two Hill-type components.Current-voltage (I/V) relationships for agonist-evoked currents wereobtained by performing 600 ms voltage steps (−110 mV to +40 mV) in theabsence and presence of agonist. The effect of the representativecompounds of Formula I on KCNQ currents is listed in Table 1. TABLE 1Example No. EC₅₀ (μM) @ −40 mv) I_(max) (%) 18 1.46 820 48 0.619 981

[0065] Thallium Assay Methods and Results

[0066] A thallium flux assay was used to detect and characterize openersof KCNQ potassium channels. The thallium assay is generally described inInternational application WO 02/31508 published Apr. 18, 2002. Morespecifically, the thallium influx assay to detect compounds that blockor open the voltage-gated K⁺ channel KCNQ2 is described in Example IV ofthe published WO 02/31508 application.

[0067] For data analysis, the amplitude of the average of the negativecontrols was subtracted from all wells. The amplitudes of the testcompounds were then compared to the value of four standard deviations ofthe negative control wells. The lowest concentration of a test compoundsufficient to generate a signal amplitude greater than or equal to fourstandard deviations from the amplitude of the negative controls wasdefined as the minimal active concentration.

[0068] For generating EC₅₀ values, compounds were serially diluted in1:3 volume increments to produce a 10 point concentration series. EC₅₀values were calculated by fitting the resulting amplitudes to asingle-site logistic equation. EC₅₀ was defined as the concentration oftest compound required to yield 50% of the maximal response. Maximalresponse (Maximal opening) was the largest signal amplitude above thenegative control generated by any concentration of a test compound.

[0069] The following Table 2 contains data which show that compounds ofthe present invention are openers of the KCNQ channels. TABLE 2 ExampleNo. EC₅₀ (μM) 47 0.039 48 0.503 49 0.354 55 0.144 58 0.892 106 1.44 1110.98

[0070] In another embodiment, this invention includes pharmaceuticalcompositions comprising at least one compound of Formula I incombination with a pharmaceutical adjuvant, carrier or diluent.

[0071] In still another embodiment, this invention relates to a methodof treatment or prevention of disorders responsive to opening of KCNQpotassium channels in a mammal in need thereof, which comprisesadministering to said mammal a therapeutically effective amount of acompound of Formula I. Preferably, the compounds of Formula I are usefulin the treatment of treatment of migraine or a migraine attack, clusterheadaches, bipolar disorder, convulsions, mania, acute mania, epilepsy,anxiety, depression, schizophrenia, functional bowel disorders, stroke,traumatic brain injury, multiple sclerosis, neurodegenerative disordersor alleviating pain such as musculoskeletal pain, post operative pain,surgical pain, inflammatory pain, neuropathic pain such as diabeticneuropathy and pain associated with cancer and fibromyalgia.

[0072] For therapeutic use, the pharmacologically active compounds ofFormula I will normally be administered as a pharmaceutical compositioncomprising as the (or an) essential active ingredient at least one suchcompound in association with a solid or liquid pharmaceuticallyacceptable carrier and, optionally, with pharmaceutically acceptableadjutants and excipients employing standard and conventional techniques.

[0073] The pharmaceutical compositions include suitable dosage forms fororal, parenteral (including subcutaneous, intramuscular, intradermal andintravenous) bronchial or nasal administration. Thus, if a solid carrieris used, the preparation may be tableted, placed in a hard gelatincapsule in powder or pellet form, or in the form of a troche or lozenge.The solid carrier may contain conventional excipients such as bindingagents, fillers, tableting lubricants, disintegrants, wetting agents andthe like. The tablet may, if desired, be film coated by conventionaltechniques. If a liquid carrier is employed, the preparation may be inthe form of a syrup, emulsion, soft gelatin capsule, sterile vehicle forinjection, an aqueous or non-aqueous liquid suspension, or may be a dryproduct for reconstitution with water or other suitable vehicle beforeuse. Liquid preparations may contain conventional additives such assuspending agents, emulsifying agents, wetting agents, non-aqueousvehicle (including edible oils), preservatives, as well as flavoringand/or coloring agents. For parenteral administration, a vehiclenormally will comprise sterile water, at least in large part, althoughsaline solutions, glucose solutions and like may be utilized. Injectablesuspensions also may be used, in which case conventional suspendingagents may be employed. Conventional preservatives, buffering agents andthe like also may be added to the parenteral dosage forms. Particularlyuseful is the administration of a compound of Formula I directly inparenteral formulations. The pharmaceutical compositions are prepared byconventional techniques appropriate to the desired preparationcontaining appropriate amounts of the active ingredient, that is, thecompound of Formula I according to the invention. See, for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., 17th edition, 1985.

[0074] The dosage of the compounds of Formula I to achieve a therapeuticeffect will depend not only on such factors as the age, weight and sexof the patient and mode of administration, but also on the degree ofpotassium channel activating activity desired and the potency of theparticular compound being utilized for the particular disorder ofdisease concerned. It is also contemplated that the treatment and dosageof the particular compound may be administered in unit dosage form andthat the unit dosage form would be adjusted accordingly by one skilledin the art to reflect the relative level of activity. The decision as tothe particular dosage to be employed (and the number of times to beadministered per day is within the discretion of the physician, and maybe varied by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect.

[0075] A suitable dose of a compound of Formula I or pharmaceuticalcomposition thereof for a mammal, including man, suffering from, orlikely to suffer from any condition as described herein is an amount ofactive ingredient from about 0.01 μg/kg to 10 mg/kg body weight. Forparenteral administration, the dose may be in the range of 0.1 μg/kg to1 mg/kg body weight for intravenous administration. For oraladministration, the dose may be in the range about 0.1 μg/kg to 5 mg/kgbody weight. The active ingredient will preferably be administered inequal doses from one to four times a day. However, usually a smalldosage is administered, and the dosage is gradually increased until theoptimal dosage for the host under treatment is determined.

[0076] However, it will be understood that the amount of the compoundactually administered will be determined by a physician, in the light ofthe relevant circumstances including the condition to be treated, thechoice of compound of be administered, the chosen route ofadministration, the age, weight, and response of the individual patient,and the severity of the patient's symptoms.

[0077] The following examples are given by way of illustration and arenot to be construed as limiting the invention in any way inasmuch asmany variations of the invention are possible within the spirit of theinvention.

Description of Specific Embodiments

[0078] Unless otherwise stated, solvents and reagents were used directlyas obtained from commercial sources, and reactions were performed undera nitrogen atmosphere. Flash chromatography was conducted on Silica gel60 (0.040-0.063 particle size; EM Science supply). ¹H NMR spectra wererecorded on a Bruker DRX-500f at 500 MHz; a Bruker DPX-300B at 300 MHz;or a Varian Gemini 300 at 300 MHz. The chemical shifts were reported inppm on the 8 scale relative to δTMS=0. The following internal referenceswere used for the residual protons in the following solvents: CDCl₃(δ_(H) 7.26), CD₃OD (δ_(H) 3.30) and DMSO-d₆ (δ_(H) 2.50). Standardacronyms were employed to describe the multiplicity patterns: s(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), b(broad), app (apparent). The coupling constant (J) is in hertz. LC/MSwas performed on a Shimadzu LC-10AS liquid chromatograph using aSPD-10AV UV-VIS detector with Mass Spectrometry data determined using aMicromass LC Platform in positive electrospray ionization mode (ESI+).Mass Spectrometry (MS) data was obtained using a standard flow injectiontechnique on a Micromass LC Platform in positive electrospray ionizationmode (ESI+) unless otherwise noted. High resolution mass spectrometry(HRMS) data was obtained using a standard flow injection technique on aFinnigan MAT 900 mass spectrometer in electrospray ionization (ESI)mode. The analytical reverse phase HPLC method is as follows unlessotherwise noted: Column YMC ODS-A C18 S7 (3.0×50 mm), Start % B=0, Final% B=100, Gradient Time=2 min, Flow rate 5 ml/minutes. Wavelength=220 nm,Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1%TFA; and R_(t) in min. Preparative reverse phase HPLC was performed on aShimadzu LC-8A automated preparative HPLC system with detector (SPD-10AVUV-VIS) wavelength and solvent systems (A and B) the same as aboveexcept where otherwise noted.

[0079] The following LCMS conditions were employed for the analysis ofthe compounds of Examples 1-117 and are as follows:

[0080] a) YMC Xterra C18 S5 4.6×50 mm; 0-100% gradient over 3 min; 4mL/min flow rate

[0081] b) YMC ODS-A C18 S7 3.0×50 mm; 0-100% gradient over 2 min; 5mL/min flow rate

[0082] c) YMC ODS S7 3.0×50 mm; 0-100% gradient over 2 min; 5 mL/minflow rate

[0083] d) YMC Xterra C18 S7 3.0×50 mm; 0-100% gradient over 2 min; 4mL/min flow rate

[0084] e) 2Primeshere C18-HC 4.6×30 mm; (5 mM NH₄OAc) 0-100% gradientover 2 min; 4 mL/min flow rate

[0085] f) YMC ODS-A C18 S5 4.6×33 mm; 0-100% gradient over 2 min; 5mL/min flow rate

Preparation of Intermediates Preparation 1

[0086] Preparation of(R)-2-Amino-2-(3-morpholin-4-ylmethyl-phenyl)-ethanol Hydrochloride

[0087] Step A: 4-(3-Vinyl-benzyl)-morpholine

[0088] To the solution of 3-vinyl benzaldehyde (5 g, 38 mmol) andmorpholine (3.0 mL, 52 mmol) in dichloromethane (126 ml) was addedsodium triacetoxyborohydride (19.2 g, 92 mmol) in portion at 0° C.followed by acetic acid (2.3 mL, 40 mmol). After the addition, reactionmixture was raised to room temperature and stirred at room temperatureovernight. The reaction mixture was diluted with dichloromethane washedwith 1N NaOH and extracted with dichloromethane 3 times. The combinedorganic layer was dried over magnesium sulfate and concentrated undervacuum to give the title compound as pale yellow oil (7.2 g, 93% yield)

[0089]¹H NMR (400 MHz, CDCl₃): δ 7.18-7.35 (m, 4H), 6.70 (dd, J=11, 18Hz, 1H), 5.75 (d, J=18, 1H), 5.24 (d, J=11, 1H), 3.71 (t, J=5 Hz, 4H),3.50 (s, 2H), 2.45 (t, J=5 Hz, 4H).

[0090] Step B:(R)-[2-Hydroxy-1-(3-morpholin-4-ylmethyl-phenyl)-ethyl]-carbamic AcidTert-Butyl Ester

[0091] Sodium hydroxide (3.13 g, 78 mmol) was dissolved in water (190mL) and 9 mL of this solution was used to dissolve potassium osmium (VI)oxide dihydrate (387 mg, 4 mol %) to get a purple suspension. The restof the sodium hydroxide solution was treated with t-butyl carbamate(9.16 g, 78 mmol) in n-propanol (89 mL), followed by addition of t-butylhypochlorite (8.86 mL, 78 mmol). This solution was stirred for 5 minutesat 0° C., then hydroquinidine 1,4-phthalazinediyl diether (1.22 g, 6 mol%) in n-propanol (89 mL) was added, followed by solution of4-(3-vinyl-benzyl)-morpholine (5.3 g, 26 mmol) in n-propanol (89 mL) andsolution of potassium osmium (VI) oxide dihydrate previously made. Thereaction mixture was stirred at 0° C. for 20 min. The reaction mixturewas diluted with saturated sodium sulfite solution and the organic layerwas separated. The aqueous layer was extracted with dichloromethanetwice. The combined organic layer was dried over magnesium sulfate,concentrated under vacuum. The crude product was purified by flashchromatography with gradient from 35% acetone/hexanes to 45%acetone/hexanes over 20 min. to afford the title compound as a stickyoil (2.1 g, 24% yield).

[0092]¹H NMR (400 MHz, CDCl₃): δ 7.17-7.31 (m, 4H), 5.30 (d, J=7, 11H),4.75 (s, 1H), 3.85 (m, 2H), 3.69 (t, J=5 Hz, 4H), 3.48 (s, 2H), 2.43 (t,J=5 Hz, 4H), 1.43 (s, 9H).

[0093] MS (M+H)⁺337

[0094] Step C: (R)-2-Amino-2-(3-morpholin-4-ylmethyl-phenyl)-ethanolHydrochloride

[0095] (R)-[2-Hydroxy-1-(3-morpholin-4-ylmethyl-phenyl)-ethyl]-carbamicacid tert-butyl ester (2.1 g, 6.25 mmol) in methanol (22 mL) was addedhydrochloric acid (2.0M in ethyl ether) (10.88 mL, 21.8 mmol) andreaction mixture was stirred at room temperature for 5 hr. The reactionmixture was concentrated under vacuum to provide the title compound as apale green solid (quantitative yield).

[0096]¹H NMR (400 MHz, CD₃OD): δ 7.70 (s, 1H), 7.57-7.62 (m, 3H), 4.41(m, 3H), 3.78-4.10 (m, 6H), 3.18-3.39 (m, 4H).

[0097] MS (M+H)⁺237

Preparation 2

[0098] Preparation of (R)-2-Amino-2-(3-morpholin-4-yl-phenyl)-ethanolHydrochloride

[0099] Step A: 4-(3-Vinyl-phenyl)-morpholine

[0100] Mixture of 3-bromo-styrene (11.2 g, 61.2 mmol), morpholine (123mL), palladium acetate (343 mg, 2.5 mol %), di-t-butyl-biphenylphosphine(911 mg, 5 mol %), sodium t-butyloxide (6.47 g, 67.4 mmol) was stirredat 80° C. in a sealed tube for 30 minutes. After cooling down, thereaction mixture was diluted with dichloromethane (250 mL) and washedwith water (100 mL). The aqueous layer was extracted withdichloromethane (2×125 mL) and the combined organic layer was dried overmagnesium sulfate and concentrated under vacuum. The crude product waspurified by Flash Chromatography of Biotage with 30% EthylAcetate/Hexanes. The title compound was obtained as pale yellow clearoil (10.7 g, 93% yield).

[0101]¹H NMR (CDCl₃): 3.18 (m, 4H), 3.87 (m, 4H), 5.23 (d, 1H), 5.73 (d,1H), 6.69 (dd, 1H), 6.84 (m, 1H), 6.96 (m, 2H), 7.25 (m, 1H).

[0102] MS (M+H)⁺190

[0103] Step B:[(R)-2-Hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]-carbamic AcidTert-Butyl Ester

[0104] Sodium hydroxide (275 mg, 6.88 mmol) was dissolved in water (38.2mL) and 1.8 mL of this solution was used to dissolve potassium osmium(VI) oxide dihydrate (80 mg, 4 mol %) to get a purple suspension. Therest of the sodium hydroxide solution was treated with t-butyl carbamate(1.86 g, 15.9 mmol) in n-propanol (21 mL), followed by addition oft-butyl hypochlorite (1.8 mL, 15.7 mmol). This solution was stirred for5 minutes then hydroquinidine 1,4-phthalazinediyl diether (210 mg, 5 mol%) in n-propanol (18 mL) was added, followed by solution of4-(3-vinyl-phenyl)-morpholine (1 g, 5.3 mmol) in n-propanol (18 mL) andsolution of potassium osmium (VI) oxide dihydrate previously made. Thereaction mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with water (50 mL), extracted with dichloromethane(3×200 mL). The combined organic layer was dried over magnesium sulfate,concentrated under vacuum. The crude product was purified by flashchromatography with 30% acetone/hexanes twice and 25% acetone/hexanesonce to afford the title compound as a white solid (810 mg, 48% yield).

[0105]¹H NMR (CDCl₃): 1.43 (broad s, 9H), 3.16 (m, 4H), 3.84 (m, 4H),4.71 (broad s, 1H), 5.22 (broad d, 1H), 6.83 (m, 3H), 7.25 (m, 1H).

[0106] MS (M+H)⁺323

[0107] Step C: (R)-2-Amino-2-(3-morpholin-4-yl-phenyl)-ethanolHydrochloride

[0108] (R)-2-Hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]-carbamic acidtert-butyl ester (500 mg, 1.55 mmol) in methanol (3.1 mL) was addedhydrochloric acid (1.0 M in ethyl ether) (4.65 mL, 4.65 mmol) andreaction mixture was stirred at room temperature for 24 hrs. Thereaction mixture was concentrated under vacuum to provide the titlecompound as yellow solid (457 mg, quantitative yield) ready for nextstep without any further purification.

[0109] MS (M+H)⁺223.

Preparation 3

[0110] Preparation of(R)-2-Amino-2-(4-fluoro-3-morpholin-4-yl-phenyl)-ethanol

[0111] Step A: 2-Bromo-1-fluoro-4-vinyl-benzene

[0112] To a suspension of Ph₃PCH₃Br (57 g) in THF (240 mL) at 0° C. wasdropwise added n-BuLi (1.6 N, 100 mL). The resulting mixture was allowedto warm to room temperature and stirred for 1 h. After recooling to 0°C., a solution of 3-bromo-4-fluoro-benzaldehyde (20.3 g) in THF (20 mL)was added. The resulting mixture was allowed to warm to room temperatureand stirred for 1 h. The reaction mixture was quenched with water,concentrated, and extracted with methylene chloride. The combinedorganic layer was dried over magnesium sulfate, concentrated undervacuum. The crude product was purified by flash chromatography elutingwith 10% ethyl acetate in hexanes to give the title compound as an oil(18 g).

[0113]¹H NMR (CDCl₃): δ 7.59-7.56 (m, 1H), 7.31-7.27 (m, 1H), 7.05 (t,J=8.4 Hz, 1H), 6.65 (dd, J=17.7, 11.1 Hz, 1H), 6.55 (d, J=17.4 Hz, 1H),5.28 (d, J=10.8 Hz, 1H).

[0114] Step B: 4-(2-Fluoro-5-vinyl-phenyl)-morpholine

[0115] A mixture of 2-Bromo-1-fluoro-4-vinyl-benzene (8 g), morpholine(20 mL), Pd₂(dba)₃ (1.83 g), di-t-butyl-biphenylphosphine (1.2 g), K₃PO₄(17 g) in DME (60 mL) was stirred at reflux for 4 h. The reactionmixture was cooled down to room temperature, diluted with methylenechloride, and filtered. The filtrate was concentrated in vacuo. Thecrude product was purified by Flash Chromatography of Biotage elutingwith 7% ethyl acetate in hexanes to give the title compound as an oil (5g).

[0116]¹H NMR (CDCl₃): δ 7.24-6.93 (m, 3H), 6.68 (dd, J=17.7, 10.8 Hz,1H), 5.66 (d, J=17.4 Hz, 1H), 5.22 (d, J=10.8 Hz, 1H). 3.88 (m, 4H),3.10 (m, 4H). MS (M+H)⁺208.

[0117] Step C:(R)-4-of[1-(Fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-carbamicAcid Tert-Butyl Ester

[0118] Sodium hydroxide (3.6 g) was dissolved in water (220 mL) and 10mL of this solution was used to dissolve potassium osmium (VI) oxidedihydrate (434 mg) to get a purple suspension. The rest of the sodiumhydroxide solution was treated with t-butyl carbamate (10.666 g) inn-propanol (120 mL), followed by addition of t-butyl hypochlorite (11mL). This solution was stirred for 5 min, then hydroquinidine1,4-phthalazinediyl diether (1466 mg) in n-propanol (120 mL) was added,followed by a solution of 4-(2-Fluoro-5-vinyl-phenyl)-morpholine (5 g)in n-propanol (206 mL) and a solution of potassium osmium (VI) oxidedihydrate previously made. The reaction mixture was stirred at roomtemperature for 0.5 h. The reaction mixture was quenched with saturatedNa₂SO₃ solution. After concentration, the residue was extracted withethyl acetate. The combined organic layers were dried over magnesiumsulfate, concentrated under vacuum. The crude product was purified byflash chromatography eluting with 33% ethyl acetate in hexanes to givethe title compound as a solid (2.2 g).

[0119]¹H NMR (CDCl₃): δ 7.03-6.83 (m, 3H), 5.19 (br s, 1H0, 4.68 (br s,1H), 3.87 (m, 6H), 3.09 (m, 4H), 1.44 (s, 9H).

[0120] MS (M+H)⁺341.

[0121] Step D: (R)-2-Amino-2-(4-fluoro-3-morpholin-4-yl-phenyl)-ethanol

[0122] A solution of TFA (5 mL) and(R)-[1-(fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-carbamic acidtert-butyl ester (1.2 g) in methylene chloride (15 mL) was stirred for 2h. After concentration, the residue was neutralized with 10 N NaOH andextracted with methylene chloride. The organic layer was washed withbrine, dried over Na₂SO₄, and concentrated in vacuo to give the titlecompound as a solid (720 mg).

[0123]¹H NMR (CDCl₃): δ 7.07-6.87 (m, 3H), 4.04-4.00 (m, 1H), 3.87-3.84(m, 4H), 3.73-3.68 (m, 1H), 3.55-3.52 (m, 1H), 3.09-3.06 (m, 4H).

[0124] MS (M+H)⁺241.

Preparation 4

[0125] Preparation of (R)-2-Amino-2-naphthalen-2-yl-ethanolHydrochloride

[0126] Step A: (R)-(2-Hydroxy-1-naphthalen-2-yl-ethyl)-carbamic AcidTert-Butyl Ester

[0127] Sodium hydroxide (1.89 g, 16 mmol) was dissolved in water (115mL) and 5.4 mL of this solution was used to dissolve potassium osmium(VI) oxide dihydrate (240 mg) to get a purple suspension. The rest ofthe sodium hydroxide solution was treated with t-butyl carbamate (5.580g, 47.1 mmol) in n-propanol (54 mL), followed by addition of t-butylhypochlorite (5.4 mL, 47.1 mmol). This solution was stirred for 5 min,then hydroquinidine 1,4-phthalazinediyl diether (630 mg) in n-propanol(54 mL) was added, followed by a solution of 2-vinylnaphthalene (2.5 g,16 mmol) in n-propanol (54 mL) and a solution of potassium osmium (VI)oxide dihydrate previously made. The reaction mixture was stirred atroom temperature for 0.5 hr. The reaction mixture was quenched withsaturated NaHSO₃ solution. After concentration, the residue wasextracted with ethyl acetate. The combined organic layer was dried overmagnesium sulfate, concentrated under vacuum. The crude product waspurified by flash chromatography with 20% ethyl acetate in hexanes togive the title compound (2.6 g) as a solid.

[0128]¹H NMR (CDCl₃): δ 7.83-7.74 (m, 4H), 7.47-7.37 (m, 3H), 5.39 (brs, 1H), 4.91 (br s, 1H), 3.90 (d, J=3.9 Hz, 2H), 1.44 (s, 9H).

[0129] MS (M+H)⁺288.

[0130] Step B: (R)-2-Amino-2-naphthalen-2-yl-ethanol Hydrochloride

[0131] (R)-(2-Hydroxy-1-naphthalen-2-yl-ethyl)-carbamic acid tert-butylester (2.5 g) and 9 mL of 4 N HCl in ethyl acetate at 50° C. was stirredfor 2 h. After concentration, the residue was neutralized with 10 N NaOHand extracted with methylene chloride. The organic layer was washed withbrine, dried over Na₂SO₄, and concentrated to give the title compound(1.2 g) as a solid which was used in the next step without furtherpurification.

[0132] MS (M+H)⁺188.

Preparation 5

[0133] Preparation of (R)-2-Amino-2-(7-methoxy-naphthalen-2-yl)-ethanol

[0134] Step A: Trifluoro-methanesulfonic Acid 7-methoxy-naphthalen-2-ylEster

[0135] To a solution of 7-methoxy-naphthalen-2-ol (17.4 g) and pyridine(40 mL) in methylene chloride (150 mL) at 0° C. was added a solution oftrifluoromethanesulfonic anhydride (32.4 g) in CH₂Cl₂ (15 mL). Afterstirring for 0.5 h, the reaction mixture was warmed to rt and stirredfor 1 h. The reaction was quenched with water carefully. The organiclayer was washed with 10% H₃PO₄, dried over MgSO₄. After concentration,the crude product was purified by flash chromatography eluting with 20%ethyl acetate in hexanes to give the title compound as an oil (28 g).

[0136]¹H NMR (CDCl₃): δ 7.83-7.74 (m,2H), 7.63 (d, J=2.4 Hz, 1H),7.24-7.12 (m, 3H), 3.92 (s, 3H).

[0137] Step B: 2-Methoxy-7-vinyl-naphthalene

[0138] To a mixture of (Ph₃P)₂PdCl₂ (1.752 g), LiCl (6.36 g), andtrifluoromethanesulfonic acid 7-methoxy-naphthalen-2-yl ester (15.3 g)was added dropwise tributyl(vinyl)tin (19.02 g). The resulting mixturewas stirred over 4 h at 90° C. The reaction was quenched with water andextracted with CH₂Cl₂. The organic layer was washed with water and driedover MgSO₄. After concentration, the crude product was purified by flashchromatography eluting with 20% ethyl acetate in hexanes to give thetitle compound as an oil (9 g).

[0139]¹H NMR (CDCl₃): δ 7.72-7.65 (m,2H), 7.49 (dd, J=8.7, 1.8 Hz, 1H),7.11-7.08 (m, 3H), 6.90 (dd, J=17.4, 10.8 Hz, 1H), 5.88 (d, J=17.7 Hz,1H), 5.33 (d, J=10.8 Hz, 1H), 3.92 (s, 3H).

[0140] MS (M+H)⁺185.

[0141] Step C:(R)-[2-Hydroxy-1-(7-methoxy-naphthalen-2-yl)-ethyl]-carbamic AcidTert-Butyl Ester

[0142] Sodium hydroxide (1.8 g) was dissolved in water (10 mL) and 5 mLof this solution was used to dissolve potassium osmium (VI) oxidedihydrate (217 mg) to get a purple suspension. The rest of the sodiumhydroxide solution was treated with t-butyl carbamate (5.333 g) inn-propanol (60 mL), followed by addition of t-butyl hypochlorite (5.5mL). This solution was stirred for 5 min, then hydroquinidine1,4-phthalazinediyl diether (733 mg) in n-propanol (60 mL) was added,followed by a solution of 2-methoxy-7-vinyl-naphthalene (2 g) inn-propanol (103 mL) and a solution of potassium osmium (VI) oxidedihydrate previously made. The reaction mixture was stirred at roomtemperature for 0.5 h. The reaction mixture was quenched with saturatedNa₂SO₃ solution. After concentration, the residue was extracted withethyl acetate. The combined organic layers were dried over magnesiumsulfate and concentrated under vacuum. The crude product was purified byflash chromatography eluting with 33% ethyl acetate in hexanes to givethe title compound as a solid (1.585 g).

[0143] Step D: (R)-2-Amino-2-(7-methoxy-naphthalen-2-yl)-ethanol

[0144] A solution of TFA (8 mL) and(R)-[2-hydroxy-1-(7-methoxy-naphthalen-2-yl)-ethyl]-carbamic acidtert-butyl ester (1.268 g) in methylene chloride (24 mL) was stirred for2 h. After concentration, the residue was neutralized with 10 N NaOH andextracted with methylene chloride. The organic layer was washed withbrine, dried over Na₂SO₄, and concentrated to give the title compound asa solid (860 mg).

Preparation 6

[0145] Preparation of (3R,2S)-3-Amino-3-naphthalen-2-yl-propane-1,2-diol

[0146] Step A:(1R,2S)-3-tert-Butoxycarbonylamino-2-hydroxy-3-naphthalen-2-yl-propionicAcid Methyl Ester

[0147] Sodium hydroxide (3.6 g) was dissolved in water (220 mL) and 10mL of this solution was used to dissolve potassium osmium (VI) oxidedihydrate (2434 mg) to get a purple suspension. The rest of the sodiumhydroxide solution was treated with t-butyl carbamate (10.666 g) inn-propanol (120 mL), followed by addition of t-butyl hypochlorite (11mL). This solution was stirred for 5 min, then hydroquinidine1,4-phthalazinediyl diether (1466 mg) in n-propanol (120 mL) was added,followed by a solution of 3-naphthalen-2-yl-acrylic acid methyl ester (5g) in n-propanol (206 mL) and a solution of potassium osmium (VI) oxidedihydrate previously made. The reaction mixture was stirred at roomtemperature for 0.5 h. The reaction mixture was quenched with saturatedNaHSO₃ solution. After concentration, the residue was extracted withethyl acetate. The combined organic layer was dried over magnesiumsulfate, concentrated under vacuum. The crude product was purified byflash chromatography with 33% ethyl acetate in hexanes to give the titlecompound (7.3 g) as a solid.

[0148]¹H NMR (CDCl₃): δ 7.84-7.79 (m, 4H), 7.50-7.43 (m, 3H), 5.53 (d,J=8.8 Hz, 1H), 45.38 (d, J=8.8 Hz, 1H), 4.56 (br s, 1H), 3.85 (s, 3H),3.22 (br s, 1H), 1.44 (s, 9H).

[0149] Step B: (1R,2S)-(2,3-Dihydroxy-1-naphthalen-2-yl-propyl)-carbamicAcid Tert-Butyl Ester

[0150] To a solution of(1R,2S)-3-tert-butoxycarbonylamino-2-hydroxy-3-naphthalen-2-yl-propionicacid methyl ester (345 mg) and MeOH (96 mg) in ether (10 mL) was addedLiBH₄ (88 mg). The resulting mixture was refluxed for 0.5 h. Aftercooling to room temperature, the reaction mixture was quenched with 1 NHCl. The organic layer was washed with water, dried over MgSO₄, andconcentrated in vacuo. The crude product was purified by flashchromatography eluting with 33% ethyl acetate in hexanes to give thetitle compound as a solid (100 mg).

[0151]¹H NMR (CDCl₃): δ 7.84-7.76 (m, 4H), 7.48-7.40 (m, 3H), 5.44 (brs, 1H), 4.98 (br s, 1H), 4.10 (br s, 1H), 3.59 (d, J=6 Hz, 2H), 1.44 (s,9H). MS (M+H)⁺318.

[0152] Step C: (3R,2S)-3-Amino-3-naphthalen-2-yl-propane-1.2-diol

[0153] A solution of TFA (5 mL) and(1R,2S)-(2,3-dihydroxy-1-naphthalen-2-yl-propyl)-carbamic acidtert-butyl ester (1.72 g) in methylene chloride (15 mL) was stirred for2 h. After concentration, the residue was neutralized with 10 N NaOH andextracted with methylene chloride. The combined organic layer was washedwith brine, dried over Na₂SO₄, and concentrated in vacuo to give thetitle compound as a solid (1.1 g).

[0154]¹H NMR (CDCl₃): δ 7.83-7.75 (m, 4H), 7.48-7.44 (m, 3H), 4.09 (d,J=7 Hz, 1H), 3.82-3.79 (m, 1H), 3.64 (dd, J=11.5, 3 Hz, 1H), 3.53 (dd,J=11.5, 4.5 Hz, 1H).

[0155] MS (M+H)⁺218.

Preparation 7

[0156] Preparation of 2-Amino-2-(3-pyridin-3-yl-phenyl)-ethanol

[0157] Step A: 2-(3-Bromo-phenyl)-oxirane

[0158] 1-Bromo-3-vinyl-benzene (5 g, 27.3 mmol) and 3-cyanopyridine (551mg, 2.7 mmol) were added in CH₂Cl₂ (25 mL), Methyltrioxorhenium (VII)(34 mg, 0.137 mmol) and hydrogen peroxide (30%) (6.2 mL, 54.6 mmol) wereadded and the reaction mixture was stirred at room temperaute for 18 h.Sodium sulfite 1M (10 mL) and saturated sodium bicarbonate were added,the aqueous layer was extracted with CH₂Cl₂, and the combined organiclayers were dried over anhydrous magnesium sulfate, filtered. Thefiltrate was concentrated in vacuo to provide the title compound asclear oil ((5.05 g, 93%).

[0159]¹H NMR (CDCl₃): δ 2.75 (dd, J=2.5, 5.3 Hz,1H), 3.14 (dd, J=4.0,5.5 Hz,1H), 3.82 (dd, J=2.5, 4.0 Hz,1H), 7.15-7.25 (m, 2H), 7.35-7.45(m, 2H).

[0160] Step B: 2-Amino-2-(3-bromo-phenyl)-ethanol

[0161] To a solution of 2-(3-bromo-phenyl)-oxirane (2.5 g, 12.6 mmol) inCH₂Cl₂ (20 mL) was added azidotrimethylsilane (2.5 mL, 18.84 mmol),followed by aluminium isopropoxide (256 mg, 1.26 mmol). The reactionmixture was stirred at room temperature for 18 h. Sodium potassiumtartrate 1M (30 mL) was added, the aqueous layer was extracted withCH₂Cl₂, and the organic layers were dried over anhydrous magnesiumsulfate and filtered. The filtrate was concentrated in vacuo, and thecrude compound is purified by flash chromatography (10% EtOAc/Hex) toprovide 2-azido-2-(3-bromo-phenyl)-ethanol (876 mg, 29%). To a solutionof 2-azido-2-(3-bromo-phenyl)-ethanol (876 mg) in THF (10 mL) was addedpolymer supported triphenylphosphine (3 mmol/g) (2 g, 6 mmol), and themixture was heated to 60° C. for 30 min. The polymer was then filteredand washed with CH₂Cl₂. The polymer was suspended in THF (20 mL) andconcentrated NH₄OH (10 mL) was added, and this mixture was agitated for24 h. The polymer was filtered and the liquid phase was evaporated invacuo to afford the title compound (110 mg, 14%).

[0162]¹H NMR (CDCl₃,400 MHz): δ 2.75 (dd, J=2.5, 5.3 Hz,1H), 3.14 (dd,J=4.0, 5.5 Hz,1H), 3.82 (dd, J=2.5, 4.0 Hz,1H), 7.15-7.25 (m, 2H),7.35-7.45 (m, 2H).

[0163] Step C: [1-(3-Bromo-phenyl)-2-hydroxy-ethyl]-carbamic AcidTert-Butyl Ester

[0164] To a solution of 2-amino-2-(3-bromo-phenyl)-ethanol (110 mg, 0.51mmol) in CH₂Cl₂ (10 mL) were added Et₃N (71 μL, 0.51 mmol),di-tert-butyl dicarbonate (111 mg, 0.51 mmol), and the reaction mixturewas stirred at room temperature for 3 h. The reaction mixture was washedwith saturated NH₄Cl (20 mL), and the organic layer was dried overanhydrous magnesium sulfate and filtered. The filtrate was concentratedin vacuo to provide the title compound as a white solid.

[0165] Step D: 2-Amino-2-(3-pyridin-3-yl-phenyl)-ethanol

[0166] To a solution of [1-(3-bromo-phenyl)-2-hydroxy-ethyl]-carbamicacid tert-butyl ester (160 mg, 0.51 mmol) in ethyleneglycoldimethylether(10 mL) in a sealed tube were added pyridine-3-boronic acid (82 mg, 0.66mmol), cesium carbonate (500 mg, 1.53 mmol) and water (2 mL). Argon wasbubbled through the solution for 10 min, and Pd(PPh₃)₄ (30 mg, 0.025mmol) was added. The reaction mixture was heated at 100° C. for 6 h. Thereaction mixture was cooled down to room temperature, and ethyl acetate(20 mL) was added. The reaction mixture was washed with saturated NH₄Cl(2×10 mL), and the organic layer was dried over anhydrous magnesiumsulfate, filtered. The filtrate was concentrated in vacuo, and the crudeproduct was diluted in CH₂Cl₂ (8 mL) and trifluoroacetic acid (2 mL).The reaction mixture was agitated for 1 h and concentrated in vacuo. Theresidue was purified by solid phase extraction (SCX cartridge, silca gelbenzene sulfonic acid linked) to give the title product (110 mg, 100%yield) as brown oil.

[0167]¹H NMR (DMSO d₆): δ 1.28 (d, 3H, J=6.8 Hz), 4.04 (q, 1H, J=6.8Hz), 7.4-7.45 (m, 2H), 7.5-7.55 (m, 1H), 7.61 (d, 1H J=7.8 Hz), 7.72 (s,1H), 8.15 (dd, 1H, J=8.3, 2.5 Hz), 8.73 (d, 1H, J=3.3 Hz).

EXAMPLES Example 1

[0168](R)-3-(2-Fluoro-phenyl)-N-[2-hydroxy-1-(3-morpholin-4-ylmethyl-phenyl)-ethyl]-acrylamideTFA Salt

[0169] Mixture of (R)-2-Amino-2-(3-morpholin-4-ylmethyl-phenyl)-ethanolhydrochloride (30 mg, 0.10 mmol), 2-fluorocinnamic acid (15.3 mg, 0.10mmol), benzotriazol-1-yloxytris(pyrrolidino)phosphoniumhexafluorophosphate (50 mg, 0.10 mmol) and triethylamine (0.05 mL, 0.40mmol) in DMF (0.5 ml) was stirred at room temperature for 3 h. Thereaction mixture was diluted with methanol and purified by prep HPLC.The title compound was obtained as pale yellow sticky oil.

[0170] HPLC rt: 1.05 min (method d)

[0171]¹H NMR (500 MHz, CD₃OD): δ 7.69-7.62 (m, 2H), 7.55-7.49 (m, 3H),7.43-7.39 (m, 2H), 7.25-7.14 (m, 2H), 6.85 (d, J=15, 1H), 5.10 (t, J=5,1H), 4.37 (d, J=5, 2H), 4.11-3.97 (m, 2H), 3.84 (d, J=10, 2H), 3.77-3.65(m, 2H), 3.45-3.14 (m, 4H).

[0172] MS (M+H)⁺385

Examples 2-13

[0173] Examples 2-13 were prepared from the appropriate correspondingacids using the same general procedure as described in Example 1. HPLCMass Example rt(min), (M + H)⁺ No. Structure Chemical Name method m/z 2

(R)-3-(3-Fluoro-phenyl)-N-[2-hy- droxy-1-(3-morpholin-4-ylmeth-yl-phenyl)-ethyl]-acryl- amide 1.21(a) 385 3

(R)-3-(4-Fluoro-phenyl)-N-[2-hy- droxy-1-(3-morpholin-4-ylmeth-yl-phenyl)-ethyl]-acryl- amide 1.18(a) 385 4

(R)-3-(2,4-Difluoro-phenyl)-N-[2-hy- droxy-1-(3-morpho-lin-4-ylmethyl-phen- yl)-ethyl]-acrylamide 1.24(a) 403 5

(R)-3-(2,3-Difluoro-phenyl)-N-[2-hy- droxy-1-(3-morpho-lin-4-ylmethyl-phen- yl-ethyl]-acrylamide 1.24(a) 403 6

(R)-3-(2,5-Difluoro-phenyl)-N-[2-hy- droxy-1-(3-morpho- lin-4-ylmethyl-phenyl)-ethyl]-acrylamide 1.20(a) 403 7

(R)-3-(2,6-Difluoro-phenyl)-N-[2-hy- droxy-1-(3-morpho- lin-4-ylmethyl-phenyl)-ethyl]-acrylamide 1.16(a) 403 8

(R)-3-(3,4-Difluoro-phenyl)-N-[2-hy- droxy-1-(3-morpho- lin-4-ylmethyl-phenyl)-ethyl]-acrylamide 1.25(a) 403 9

(R)-3-(2-Chloro-4-fluoro- phenyl)-N-[2-hydroxy-1-(3-morpho-lin-4-ylmethyl- phenyl)-ethyl]-acrylamide 1.37(a) 419 10

(R)-3-(4-Chloro-2-fluoro- phenyl)-N-[2-hydroxy-1-(3-morpho-lin-4-ylmethyl- phenyl)-ethyl]-acrylamide 1.41(a) 419 11

(R)-N-[2-Hydroxy-1-(3-morpho- lin-4-ylmethyl-phenyl)-ethyl]-3-thiophen-3-yl- acrylamide 1.01(a) 373 12

(R)-N-[2-Hydroxy-1-(3-morpho- lin-4-ylmethyl-phenyl)-ethyl]-3-thiophen-2-yl- acrylamide 1.02(a) 373 13

(R)-3-Furan-2-yl-N-[2-hy- droxy-1-(3-morpholin-4-yl-methyl-phenyl)-ethyl]-acryl- amide 0.88(a) 357

Example 14

[0174](R)-N-[2-Hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-acrylamide

[0175] Mixture of (R)-2-Amino-2-(3-morpholin-4-yl-phenyl)-ethanolhydrochloride (70 mg, 0.24 mmol), cinnamic acid (35 mg, 0.24 mmol), EDC(91 mg, 0.47 mmol), DMAP (29 mg, 0.24 mmol), triethyl amine (0.13 mL,0.95 mmol) in dichloromethane (1 mL) was stirred at room temperatureovernight. The reaction mixture was concentrated under vacuum andpurified by flash chromatography with 60% acetone/hexanes to provide thetitle compound as a white solid (57 mg, 68% yield).

[0176] HPLC rt: 1.14 min (method c)

[0177]¹H NMR (CDCl₃): δ 3.23 (m, 4H), 3.97 (m, 6H), 5.18 (m, 1H), 6.48(m, 2H), 7.10 (m, 3H), 7.30 (m, 3H), 7.50 (m, 2H), 7.69 (d, 1H).

[0178] MS (M+H)⁺353.

Examples 15-29

[0179] Examples 15-29 were prepared from the appropriate correspondingacid using the same general procedure as described in Example 14. HPLCMass Example rt(min), (M + H)⁺ No. Structure Chemical Name method m/z 15

(R)-N-[2-Hydroxy-1-(3-morpho- lin-4-yl-phenyl)-eth-yl]-3-phenyl-propion- amide 1.26(b) 355 16

(R)-3-(2-Fluoro-phenyl)-N-[2-hy- droxy-1-(3-morpho-lin-4-yl-phenyl)-eth- yl]-acrylamide 1.38(b) 371 17

(R)-3-(3-Fluoro-phenyl)-N-[2-hy- droxy-1-(3-morpho-lin-4-yl-phenyl)-eth- yl]-acrylamide 1.40(b) 371 18

(R)-3-(2,4-Difluoro- phenyl)-N-[2-hydroxy-1-(3-morpho- lin-4-yl-phen-yl)-ethyl]-acrylamide 1.46(b) 389 19

(R)-3-(2,3-Difluoro- phenyl)-N-[2-hydroxy-1-(3-morpho- lin-4-yl-phen-yl)-ethyl]-acrylamide 1.48(b) 389 20

(R)-3-(2,5-Difluoro- phenyl)-N-[2-hydroxy-1-(3-morpho- lin-4-yl-phen-yl)-ethyl]-acrylamide 1.44(b) 389 21

(R)-3-(3,5-Difluoro- phenyl)-N-[2-hydroxy-1-(3-morpho- lin-4-yl-phen-yl)-ethyl]-acrylamide 1.49(b) 389 22

(R)-3-(2-Chloro-4-fluoro- phenyl)-N-[2-hydroxy-1-(3-morpho-lin-4-yl-phen- yl)-ethyl]-acrylamide 1.59(b) 405 23

(R)-3-(2-Chloro-6-fluoro- phenyl)-N-[2-hydroxy-1-(3-morpho-lin-4-yl-phen- yl)-ethyl]-acrylamide 1.32(c) 405 24

(R)-N-[2-Hydroxy-1-(3-morpho- lin-4-yl-phenyl)-eth- yl]-3-(4-tri-fluoromethyl-phenyl)-propion- amide 1.47(c) 421 25

(R)-3-(2,6-Difluoro- phenyl)-N-[2-hydroxy-1-(3-morpho- lin-4-yl-phen-yl)-ethyl]-acrylamide 1.40(b) 389 26

(R)-3-(4-Chloro-2-fluoro- phenyl)-N-[2-hydroxy-1-(3-morpho-lin-4-yl-phen- yl)-ethyl]-acrylamide 1.44(c) 405 27

(R)-N-[2-Hydroxy-1-(3-morpho- lin-4-yl-phenyl)-eth- yl]-3-p-tolyl-acryl-amide 1.30(c) 367 28

(R)-N-[2-Hydroxy-1-(3-morpho- lin-4-yl-phenyl)-eth- yl]-3-m-tolyl-acryl-amide 1.31(c) 367 29

(R)-N-[2-Hydroxy-1-(3-morpho- lin-4-yl-phenyl)-eth- yl]-3-o-tolyl-acryl-amide 1.28(c) 367

Example 30

[0180](R)-3-(2-Chloro-phenyl)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-acrylamide

[0181] A mixture of(R)-2-amino-2-(4-fluoro-3-morpholin-4-yl-phenyl)-ethanol (0.1 mmol),2-chloro-cinnamic acid (0.1 mmol), EDC.HCl (0.2 mmol), DMAP (0.1 mmol),triethyl amine (0.3 mmol) in dichloromethane (2 mL) was stirred at roomtemperature for 14 h. The reaction mixture was purified by flashchromatography with 5% methnol in ethyl acetate to provide the titlecompound as a solid (29 mg).

[0182] HPLC rt: 1.48 min (method d)

[0183]¹H NMR (CDCl₃): δ 8.01 (d, J=15.5 Hz, 1H), 7.49-6.87 (m, 7H), 6.50(d, J=15.5 Hz, 1H), 5.13-5.07 (m, 1H), 3.90-3.80 (m, 6H), 3.06-3.03 (m,4H).

[0184] MS (M+H)⁺405.

Examples 31-45

[0185] Examples 31-45 were prepared from the appropriate correspondingacid using the same general procedure as described in Example 30. HPLCMass Example rt(min), (M + H)⁺ No. Structure Chemical Name method m/z 31

(R)-N-[1-(4-Fluoro-3-morpho- lin-4-yl-phenyl)-2-hy-droxy-ethyl]-3-(2-fluoro- phenyl)-acrylamide 1.39(d) 389 32

(R)-N-[1-(4-Fluoro-3-morpho- lin-4-yl-phenyl)-2-hy-droxy-ethyl]-3-(3-fluoro- phenyl)-acrylamide 1.39(c) 389 33

(R)-N-[1-(4-Fluoro-3-morpho- lin-4-yl-phenyl)-2-hy-droxy-ethyl]-3-(4-fluoro- phenyl)-acrylamide 1.39(d) 389 34

(R)-N-[1-(4-Fluoro-3-morpho- lin-4-yl-phenyl)-2-hy-droxy-ethyl]-3-phenyl- acrylamide 1.35(d) 371 35

(R)-3-(4-Chloro-phenyl)-N-[1-(4-fluor- o-3-morpho-lin-4-yl-phenyl)-2-hy- droxy-ethyl]-acrylamide 1.53(d) 405 36

(R)-N-[1-(4-Fluoro-3-morpho- lin-4-yl-phenyl)-2-hy-droxy-ethyl]-3-o-tolyl-acryl- amide 1.46(d) 385 37

(R)-N-[1-(4-Fluoro-3-morpho- lin-4-yl-phenyl)-2-hy-droxy-ethyl]-3-p-tolyl-acryl- amide 1.49(d) 385 38

(R)-3-(2,4-Difluoro- phenyl)-N-[1-(4-fluoro-3-morpho-lin-4-yl-phenyl)-2-hy- droxy-ethyl]-acrylamide 1.50(d) 407 39

(R)-3-(2,5-Difluoro- phenyl)-N-[1-(4-fluoro-3-morpho-lin-4-yl-phenyl)-2-hy- droxy-ethyl]-acrylamide 1.42(d) 407 40

(R)-3-(2,6-Difluoro- phenyl)-N-[1-(4-fluoro-3-morpho-lin-4-yl-phenyl)-2-hy- droxy-ethyl]-acrylamide 1.40(d) 407 41

(R)-3-(3,4-Difluoro- phenyl)-N-[1-(4-fluoro-3-morpho-lin-4-yl-phenyl)-2-hy- droxy-ethyl]-acrylamide 1.45(d) 407 42

(R)-3-(3,5-Difluoro- phenyl)-N-[1-(4-fluoro-3-morpho-lin-4-yl-phenyl)-2-hy- droxy-ethyl]-acrylamide 1.42(d) 407 43

(R)-3-(4-Chloro-2-fluoro- phenyl)-N-[1-(4-fluoro-3-morpho-lin-4-yl-phenyl)-2-hy- droxy-ethyl]-acrylamide 1.52(d) 423 44

(R)-3-(2-Chloro-4-fluoro- phenyl)-N-[1-(4-fluoro-3-morpho-lin-4-yl-phenyl)-2-hy- droxy-ethyl]-acrylamide 1.49(d) 423 45

(R)-3-(2-Chloro-6-fluoro- phenyl)-N-[1-(4-fluoro-3-morpho-lin-4-yl-phenyl)-2-hy- droxy-ethyl]-acrylamide 1.43(d) 423

Example 46

[0186](R)-3-(2-Fluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-acrylamide

[0187] A mixture of (R)-2-amino-2-naphthalen-2-yl-ethanol (0.2 mmol),2-fluorocinnamic acid (0.2 mmol), EDC HCl (0.4 mmol), DMAP (0.2 mmol),triethyl amine (0.6 mmol) in dichloromethane (4 mL) was stirred at roomtemperature for 14 h. The reaction mixture was purified by flashchromatography with 50% ethyl acetate in hexanes to provide the desiredproduct (56 mg) as a solid.

[0188] HPLC rt: 1.43 (method d)

[0189]¹H NMR (CD₃OD): δ 7.86-7.43 (m, 10H), 7.22-7.15 (m, 2H), 6.92 (d,J=15.9 Hz, 1H), 5.31 (t, J=6.9 Hz,1H), 3.98 (m, 2H).

[0190] MS (M+H)⁺336.

Examples 47-91

[0191] Examples 47-91 were prepared from the appropriate correspondingacid using the same general procedure as described in Example 46. HPLCMass Example rt(min), (M + H)⁺ No. Structure Chemical Name method m/z 47

(R)-3-(3-Fluoro-phenyl)-N-(2-hy- droxy-1-naphthalen-2-yl-eth-yl)-acrylamide 1.40(d) 336 48

(R)-3-(4-Fluoro-phenyl)-N-(2-hy- droxy-1-naphthalen-2-yl-eth-yl)-acrylamide 1.40(d) 336 49

(R)-N-(1-Naphthalen-2-yl-eth- yl)-3-phenyl-acrylamide 1.36(d) 318 50

(R)-3-(2-Chloro-phenyl)-N-(2-hy- droxy-1-naphthalen-2-yl-eth-yl)-acrylamide 1.46(d) 356 51

(R)-3-(3-Chloro-phenyl)-N-(2-hy- droxy-1-naphthalen-2-yl-eth-yl)-acrylamide 1.50(d) 356 52

(R)-N-(2-Hydroxy-1-naph- thalen-2-yl-ethyl)-3-o-tolyl-acryl- amide1.44(d) 332 53

(R)-N-(2-Hydroxy-1-naph- thalen-2-yl-ethyl)-3-m-tolyl-acryl- amide1.45(d) 332 54

(R)-3-(2,3-Difluoro-phen- yl)-N-(2-hydroxy-1-naph-thalen-2-yl-ethyl)-acryl- amide 1.45(d) 354 55

(R)-3-(2,4-Difluoro-phen- yl)-N-(2-hydroxy-1-naph-thalen-2-yl-ethyl)-acryl- amide 1.45(d) 354 56

(R)-3-(2,5-Difluoro-phen- yl)-N-(2-hydroxy-1-naph-thalen-2-yl-ethyl)-acryl- amide 1.44(d) 354 57

(R)-3-(2,6-Difluoro-phen- yl)-N-(2-hydroxy-1-naph-thalen-2-yl-ethyl)-acryl- amide 1.44(d) 354 58

(R)-3-(3,4-Difluoro-phen- yl)-N-(2-hydroxy-1-naph-thalen-2-yl-ethyl)-acryl- amide 1.45(d) 354 59

(R)-3-(3,5-Difluoro-phen- yl)-N-(2-hydroxy-1-naph-thalen-2-yl-ethyl)-acryl- amide 1.46(d) 354 60

(R)-3-(4-Chloro-2-fluoro-phen- yl)-N-(2-hydroxy-1-naph-thalen-2-yl-ethyl)-acryl- amide 1.54(d) 370 61

(R)-3-(2-Chloro-4-fluoro-phen- yl)-N-(2-hydroxy-1-naph-thalen-2-yl-ethyl)-acryl- amide 1.52(d) 370 62

(R)-Cyclopentane-carboxylic acid(2-hydroxy-1-naph-thalen-2-yl-ethyl)-amide 1.53(f) 284 63

(R)-Cyclohexane-carboxylic acid(2-hydroxy-1-naph-thalen-2-yl-ethyl)-amide 1.63(f) 298 64

(R)-2-Cyclopentyl-N-(2-hy- droxy-1-naphthalen-2-yl-eth- yl)-acetamide1.65(f) 298 65

(R)-2-Cyclohexyl-N-(2-hy- droxy-1-naphthalen-2-yl-eth- yl)-acetamide1.75(f) 312 66

(R)-N-(2-Hydroxy-1-naph- thalen-2-yl-ethyl)-benzamide 1.51(f) 292 67

(R)-2-Fluoro-N-(2-hydroxy-1-naph- thalen-2-yl-ethyl)-benzamide 1.52(f)310 68

(R)-3-Fluoro-N-(2-hydroxy-1-naph- thalen-2-yl-ethyl)-benzamide 1.59(f)310 69

(R)-4-Fluoro-N-(2-hydroxy-1-naph- thalen-2-yl-ethyl)-benzamide 1.57(f)310 70

(R)-2,3-Difluoro-N-(2-hy- droxy-1-naphthalen-2-yl-eth- yl)-benzamide1.57(f) 328 71

(R)-2,4-Difluoro-N-(2-hy- droxy-1-naphthalen-2-yl-eth- yl)-benzamide1.58(f) 328 72

(R)-2,5-Difluoro-N-(2-hy- droxy-1-naphthalen-2-yl-eth- yl)-benzamide1.56(f) 328 73

(R)-2,6-Difluoro-N-(2-hy- droxy-1-naphthalen-2-yl-eth- yl)-benzamide1.42(f) 328 74

(R)-3,4-Difluoro-N-(2-hy- droxy-1-naphthalen-2-yl-eth- yl)-benzamide1.65(f) 328 75

(R)-3,5-Difluoro-N-(2-hy- droxy-1-naphthalen-2-yl-eth- yl)-benzamide1.66(f) 328 76

(R)-2-(2-Fluoro-phenyl)-N-(2-hy- droxy-1-naphthalen-2-yl-eth-yl)-acetamide 1.54(f) 324 77

(R)-2-(3-Fluoro-phenyl)-N-(2-hy- droxy-1-naphthalen-2-yl-eth-yl)-acetamide 1.57(f) 324 78

(R)-2-(4-Fluoro-phenyl)-N-(2-hy- droxy-1-naphthalen-2-yl-eth-yl)-acetamide 1.58(f) 324 79

(R)-2-(2,3-Difluoro-phen- yl)-N-(2-hydroxy-1-naph-thalen-2-yl-ethyl)-acet- amide 1.59(f) 342 80

(R)-2-(2,4-Difluoro-phen- yl)-N-(2-hydroxy-1-naph-thalen-2-yl-ethyl)-acet- amide 1.60(f) 342 81

(R)-2-(2,5-Difluoro-phen- yl)-N-(2-hydroxy-1-naph-thalen-2-yl-ethyl)-acet- amide 1.57(f) 342 82

(R)-2-(2,6-Difluoro-phen- yl)-N-(2-hydroxy-1-naph-thalen-2-yl-ethyl)-acet- amide 1.54(f) 342 83

(R)-2-(3,5-Difluoro-phen- yl)-N-(2-hydroxy-1-naph-thalen-2-yl-ethyl)-acet- amide 1.64(f) 342 84

(R)-N-(2-Hydroxy-1-naph- thalen-2-yl-ethyl)-3-phenyl- propionamide1.65(f) 320 85

(R)-3-(2-Fluoro-phenyl)-N-(2-hy- droxy-1-naphthalen-2-yl-eth-yl)-propionamide 1.67(f) 338 86

(R)-3-(3-Fluoro-phenyl)-N-(2-hy- droxy-1-naphthalen-2-yl-eth-yl)-propionamide 1.65(f) 338 87

(R)-3-(4-Fluoro-phenyl)-N-(2-hy- droxy-1-naphthalen-2-yl-eth-yl)-propionamide 1.67(f) 338 88

(R)-3-(2,3-Difluoro-phen- yl)-N-(2-hydroxy-1-naph-thalen-2-yl-ethyl)-propion- amide 1.69(f) 356 89

(R)-3-(2,4-Difluoro-phen- yl)-N-(2-hydroxy-1-naph-thalen-2-yl-ethyl)-propion- amide 1.69(f) 356 90

(R)-3-(2,4-Difluoro-phen- yl)-N-(2-hydroxy-1-naph-thalen-2-yl-ethyl)-propion- amide 1.67(f) 356 91

(R)-3-(3,4-Difluoro-phen- yl)-N-(2-hydroxy-1-naph-thalen-2-yl-ethyl)-propion- amide 1.68(f) 356

Example 92

[0192](R)-3-(2,6-Difluoro-phenyl)-N-[2-hydroxy-1-(7-methoxy-naphthalen-2-yl)-ethyl]-acrylamide

[0193] A mixture of (R)-2-Amino-2-(7-methoxy-naphthalen-2-yl)-ethanol(0.1 mmol), 2,6-difluorocinnamic acid (0.1 mmol), EDC.HCl (0.2 mmol),DMAP 0.1 mmol), triethyl amine (0.3 mmol) in dichloromethane (2 mL) wasstirred at room temperature for 14 h. The reaction mixture was purifiedby flash chromatography eluting with 5% methnol in ethyl acetate toprovide the title compound as a solid (25 mg).

[0194]¹H NMR (CDCl₃): δ 7.78-7.66 (m, 4H), 7.30 (d, J=8.4 Hz, 1H),7.15-7.02 (m, H), 6.32 (d, J=15.6 Hz,1H), 5.35-5.28 (m,1H), 4.07-4.01(m, 2H), 3.90 (s, H).

[0195] MS (M+H)⁺384.

EXAMPLES 93-103

[0196] Examples 93-103 were prepared from the appropriate correspondingacid using the same general procedure as described in Example 92. HPLCMass Example rt(min), (M + H)⁺ No. Structure Chemical Name method m/z 93

(R)-3-(2-Fluoro-phenyl)-N-[2-hy- droxy-1-(7-meth-oxy-naphthalen-2-yl)-eth- yl]-acrylamide 1.54(d) 366 94

(R)-3-(3-Fluoro-phenyl)-N-[2-hy- droxy-1-(7-meth-oxy-naphthalen-2-yl)-eth- yl]-acrylamide 1.55(d) 366 95

(R)-3-(4-Fluoro-phenyl)-N-[2-hy- droxy-1-(7-meth-oxy-naphthalen-2-yl)-eth- yl]-acrylamide 1.55(d) 366 96

(R)-N-[2-Hydroxy-1-(7-meth- oxy-naphthalen-2-yl)-eth-yl]-3-phenyl-acryl- amide 1.52(d) 348 97

(R)-3-(2-Chloro-phen- yl)-N-[2-hydroxy-1-(7-meth-oxy-naphthalen-2-yl)-eth- yl]-acrylamide 1.61(d) 382 98

(R)-3-(3-Chloro-phen- yl)-N-[2-hydroxy-1-(7-methoxy-naphthalen-2-yl)-eth- yl]-acrylamide 1.65(d) 382 99

(R)-N-[2-Hydroxy-1-(7-meth- oxy-naphthalen-2-yl)-eth-yl]-3-o-tolyl-acryl- amide 1.59(d) 362 100

(R)-3-(2,3-Difluoro-phen- yl)-N-[2-hydroxy-1-(7-meth-oxy-naphthalen-2-yl)-eth- yl]-acrylamide 1.66(d) 384 101

(R)-3-(2,4-Difluoro-phen- yl)-N-[2-hydroxy-1-(7-meth-oxy-naphthalen-2-yl)-eth- yl]-acrylamide 1.64(d) 384 102

(R)-3-(2,5-Difluoro-phen- yl)-N-[2-hydroxy-1-(7-meth-oxy-naphthalen-2-yl)-eth- yl]-acrylamide 1.64(d) 384 103

(R)-3-(2-Chloro-4-fluoro- phenyl)-N-[2-hy- droxy-1-(7-methoxy-naph-thalen-2-yl)-ethyl]-acryl- amide 1.72(d) 400

Example 104

[0197](1R,2S)-3-tert-butoxycarbonylamino-2-hydroxy-3-naphthalen-2-yl-propionicAcid Methyl Ester

[0198] A solution of (3R,2S)-3-amino-3-naphthalen-2-yl-propane-1,2-diol(0.1 mmol), cinnamic acid (0.1 mmol), EDC.HCl (0.2 mmol), DMAP (0.1mmol), triethyl amine (0.3 mmol) in dichloromethane (2 mL) was stirredat room temperature for 14 h. The reaction mixture was purified by flashchromatography eluting with 5% methnol in ethyl acetate to provide thetitle compound as a solid (20 mg).

[0199] HPLC rt: 1.49 (method d)

[0200]¹H NMR (CD₃OD): δ 7.88-7.43 (m, 4H), 7.68 (d, J=15.5 Hz, 1H),7.49-7.43 (m, 5H), 7.35-7.26 (m, 3H), 6.54 (brs, 1H), 6.52 (d, J=15.5Hz, 1H), 5.45 (dd, J=8, 4, Hz, 1H), 4.21 (q, J=5.5 Hz, 1H), 3.61 (d, J=6Hz, 2H). MS (M+H)⁺370.

EXAMPLES 105-115

[0201] Examples 105-115 were prepared from the appropriate correspondingacid using the same general procedure as described in Example 104. HPLCMass Example rt(min), (M + H)⁺ No. Structure Chemical Name method m/z105

(1R,2S)-N-(2,3-Dihydroxy-1-naph- thalen-2-yl-propyl)-3-(2-fluoro-phenyl)-acrylamide 1.52(d) 366 106

(1R,2S)-3-(2-Chloro- phenyl)-N-(2,3-dihydroxy-1-naph-thalen-2-yl-propyl)-acryl- amide 1.60(d) 382 107

(1R,2S)-3-(3-Chloro- phenyl)-N-(2,3-dihydroxy-1-naph-thalen-2-yl-propyl)-acryl- amide 1.63(d) 382 108

(1R,2S)-N-(2,3-Dihydroxy-1-naph- thalen-2-yl-propyl)-3-o-tolyl-acryl-amide 1.60(d) 362 109

(1R,2S)-N-(2,3-Dihydroxy-1-naph- thalen-2-yl-propyl)-3-p-tolyl-acryl-amide 1.88(d) 362 110

(1R,2S)-3-(2,3-Difluoro-phen- yl)-N-(2,3-dihydroxy-1-naph-thalen-2-yl-propyl)-acrylamide 1.85(d) 384 111

(1R,2)-3-(2,4-Difluoro-phen- yl)-N-(2,3-dihydroxy-1-naph-thalen-2-yl-propyl)-acryl- amide 1.86(d) 384 112

(1R,2S)-3-(3,4-Difluoro-phen- yl)-N-(2,3-dihydroxy-1-naph-thalen-2-yl-propyl)-acryl- amide 1.87(d) 384 113

(1R,2S)-3-(3,5-Difluoro-phen- yl)-N-(2,3-dihydroxy-1-naph-thalen-2-yl-propyl)-acryl- amide 1.89(d) 384 114

(1R,2S)-3-(4-Chloro-2-fluoro- phenyl)-N-(2,3-di-hydroxy-1-naphthalen-2-yl-prop- yl)-acrylamide 1.94(d) 400 115

(1R,2S)-3-(2-Chloro-4-fluoro- phenyl)-N-(2,3-di-hydroxy-1-naphthalen-2-yl-prop- yl)-acrylamide 1.92(d) 400

Example 116

[0202] N-[2-Hydroxy-1-(3-pyridin-3-yl-phenyl)-ethyl]-3-phenyl-acrylamide

[0203] To a solution of cinnamic acid (0.083 mmol), amine (0.064 mmol),EDC (18.4 mg, 0.096 mmol), HOBT (13 mg, 0.096 mmol) in DMF (2 mL) wasadded diisopropylethylamine (33 μL, 0.192 mmol), and the resultingreaction mixture was stirred at room temperature for 18. The residue waspurified by preparative HPLC (Primeshere C18-HC 21.2×100 mm; (5 mMNH₄OAc) 0-100% gradient over 5 min; 20 mL/min flow rate) to afford thetitle product.

[0204] HPLC rt: 1.49 min (method e)

[0205]¹H NMR (CDCl₃): δ 4.03 (d, 3H, J=4.6 Hz), 5.29 (m, 1H), 6.51 (d,1H, J=15.7 Hz), 6.54 (s, 1H), 7.3-7.5 (m, 9H), 7.53 (s, 1H) 7.67 (d, 1H,J=15.7 Hz), 7.84 (d, 1H, J=7.8 Hz), 8.57 (dd, 1H, J=1.8, 4.8 Hz), 8.71(d, 1H, J=1.8 Hz).

[0206] Mass (M+H)⁺345.

Example 117

[0207]3-(2-Fluoro-phenyl)-N-[2-hydroxy-1-(3-pyridin-3-yl-phenyl)-ethyl]-acrylamide

[0208] To a solution of 2-fluoro-cinnamic acid (0.083 mmol), amine(0.064 mmol), EDC (18.4 mg, 0.096 mmol), HOBT (13 mg, 0.096 mmol) in DMF(2 mL) was added diisopropylethylamine (33 μL, 0.192 mmol), and theresulting reaction mixture was stirred at room temperature for 18. Theresidue was purified by preparative HPLC (Primeshere C18-HC 21.2×100 mm;(5 mM NH₄OAc) 0-100% gradient over 5 min; 20 mL/min flow rate) to affordthe title product.

[0209] HPLC rt: 1.51 min (method e)

[0210] Mass (M+H)⁺363.

What is claimed is:
 1. A compound of Formula I or a pharmaceutically acceptable salt thereof

wherein R¹ is selected from the group consisting of pyridinyl, 3-quinolinyl, 2-thienyl, furanyl, C₃₋₆ cycloalkyl and phenyl optionally substituted with substituent independently selected from the group consisting of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl, trifluoromethoxy and nitro; A is —CH═CH— or —(CH₂)_(n)—; R² is hydrogen or hydroxymethyl; n is an integer of 0, 1 or 2; R⁴ is selected from the group consisting of di(C₁₋₄ alkyl)amino, trifluoromethoxy and optionally substituted morpholin-4-yl, morpholin-4-ylmethyl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl with one or two substituents in which said substituent is independently selected from the group consisting of C₁₋₄ alkyl, aminomethyl, hydroxymethyl, chloro or fluoro; R⁵ is hydrogen or fluoro; or R⁴ and R⁵ taken together is —CH═CH—CH═CH— optionally substituted with a substituent independently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl and trifluoromethoxy; and R³, R⁶, and R⁷ are each independently hydrogen or fluoro.
 2. The compound of claim 1 having the Formula Ia or a pharmaceutically acceptable salt thereof

wherein R¹ is selected from the group consisting of pyridinyl, 3-quinolinyl, 2-thienyl, furanyl, C₃₋₆ cycloalkyl and phenyl optionally substituted with substituent independently selected from the group consisting of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl, trifluoromethoxy and nitro; A is —CH═CH— or —(CH₂)_(n)—; R² is hydrogen; n is an integer of 0, 1 or 2; R⁴ is selected from the group consisting of di(C₁₋₄ alkyl)amino, trifluoromethoxy and optionally substituted morpholin-4-yl, morpholin-4-ylmethyl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl with one or two substituents in which said substituent is independently selected from the group consisting of C₁₋₄ alkyl, aminomethyl, hydroxymethyl, chloro or fluoro; R⁵ is hydrogen or fluoro; or R⁴ and R⁵ taken together is —CH═CH—CH═CH— optionally substituted with a substituent independently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl and trifluoromethoxy; and R³, R⁶, and R⁷ are each independently hydrogen or fluoro.
 3. The compound of claim 1 selected from the group consisting of: (R)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-propionamide; (R)-3-(2-fluoro-phenyl)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]-acrylamide; (R)-3-(3-fluoro-phenyl)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]-acrylamide; (R)-3-(2,4-difluoro-phenyl)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]-acrylamide; (R)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-3-(2-fluorophenyl)-acrylamide; (R)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-3-(3-fluorophenyl)-acrylamide; (R)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-3-(4-fluorophenyl)-acrylamide; (R)-3-(2,4-difluoro-phenyl)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-acrylamide; (R)-3-(3-fluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-acrylamide; (R)-3-(4-fluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-acrylamide; (R)-3-(2,4-difluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-acrylamide; (R)-3-(3,4-difluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-acrylamide; (R)-4-fluoro-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-benzamide; (R)-2,3-difluoro-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-benzamide; (R)-2,4-difluoro-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-benzamide; (R)-3,4-difluoro-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-benzamide; (R)-2-(2,4-difluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-acetamide; (R)-3-(2-fluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-propionamide; (R)-3-(3-fluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-propionamide; (R)-3-(4-fluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-propionamide; (R)-3-(2,4-difluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-propionamide; (R)-3-(2-fluoro-phenyl)-N-[2-hydroxy-1-(7-methoxy-naphthalen-2-yl)-ethyl]-acrylamide; (R)-3-(3-fluoro-phenyl)-N-[2-hydroxy-1-(7-methoxy-naphthalen-2-yl)-ethyl]-acrylamide; (R)-3-(4-fluoro-phenyl)-N-[2-hydroxy-1-(7-methoxy-naphthalen-2-yl)-ethyl]-acrylamide; (R)-3-(2,4-difluoro-phenyl)-N-[2-hydroxy-1-(7-methoxy-naphthalen-2-yl)-ethyl]-acrylamide; (1R,2S)-N-(2,3-dihydroxy-1-naphthalen-2-yl-propyl)-3-(2-fluoro-phenyl)-acrylamide; (1R,2S)-3-(2,4-difluoro-phenyl)-N-(2,3-dihydroxy-1-naphthalen-2-yl-propyl)-acrylamide; (1R,2S)-3-(3,4-difluoro-phenyl)-N-(2,3-dihydroxy-1-naphthalen-2-yl-propyl)-acrylamide; and (1R,2S)-3-(3,5-difluoro-phenyl)-N-(2,3-dihydroxy-1-naphthalen-2-yl-propyl)-acrylamide; or a pharmaceutically acceptable salt thereof.
 4. A pharmaceutical composition for the treatment of disorders responsive to opening of KCNQ potassium channels comprising a therapeutically effective amount of the compound of claim 1 in association with a pharmaceutically acceptable carrier, adjuvant or diluent.
 5. A method for the treatment of disorders responsive to opening of the KCNQ potassium channels in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of the compound of claim
 1. 6. The method of claims 5 wherein said disorders are acute and chronic pain, migraine, neuropathic pain, bipolar disorders, convulsions, mania, epilepsy, anxiety, depression and neurodegenerative disorders. 7 The method of claim 6 wherein said disorder is migraine.
 8. The method of claim 6 wherein said disorder is neuropathic pain. 